Conversations With Prostate Cancer Experts

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David Crawford is the distinguished Professor of Surgery, Urology, and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus as well as the driving force behind PCMarkers.

Prostatepedia spoke with him about how practitioners can fine-tune prostate cancer screening.

Why did you become a doctor?

Dr. E. David Crawford: I got my interest in medicine from my family. They had a nursing home. I worked there when I was in high school and college, so I was around patients and doctors. I saw the compassion the doctors had and really liked it. I got to know a few of them.

Even though that was only a snapshot, I thought medicine would be a good thing to do. Then I got a job during college doing evaluations of people before surgery. That was how I got interested in urology.

My interest in prostate cancer began when I was at the University of California, Los Angeles, as a Fellow. I was dumbfounded that most of the patients we saw with prostate cancer were advanced and incurable.

I had an opportunity to work with Schering Corp. I did a study and got one of their drugs called Eulexin (flutamide) approved.

A man named Perry Lieber from Las Vegas came to see me. The only way he could get Eulexin (flutamide) was on my Phase III trial. He was a spokesman for Howard Hughes. He wanted to get the word out about early detection for prostate cancer. We started some of the early screening back in the 1980s in Las Vegas and in Colorado. Unfortunately, he died of prostate cancer.

This was in 1988. We didn’t know what we were doing. We had PSA; we were testing and biopsying a lot of people. At first, that was good because we found a lot of aggressive prostate cancers.

Once we filtered through those, though, we were biopsying people at lower and lower PSAs and finding prostate cancers that didn’t need to be found. There was a lot of overdiagnosis and overtreatment.

That went on for a while. Then the US Preventive Services Task Force said they think screening does work, but that it does more harm than good, so they couldn’t recommend it. (They have more recently changed their recommendations.)

That put the brakes on things, but I think it was needed. When we do too many biopsies and rebiopsies and overtreat people, we have no way to restratify them.

I think the way forward is pretty simple. It involves prostate cancer markers: blood, urine, and tissue-based markers.

But first consider who orders PSA tests in the United States: family practice doctors order 92% of PSA tests. We have to educate these family practice doctors.

I did a study a few years ago that looked at the PSA cutoff of 1.5 ng/ ml. What if you find prostate cancer in that zone of 1.5 to 4? We found that 70% of men who had their PSA analyzed had a level of less than 1.5 ng/ml and, therefore, could come back in 5 years for another one.

That’s an easy message: a PSA above 1.5 to 4 ng/ml is a danger zone. Prostate cancer marker tests come into play in men with PSAs in that gray zone of 1.5 to 4 ng/ml.

Everyone is talking about informed decision-making with these tests before a PSA is performed, but this is not going to happen. Family practice doctors have more significant things to talk about with their patients: obesity, hypertension, or diabetes. They don’t get informed decision to check your cholesterol, your blood pressure, or your weight. They get informed decision after the fact.

I think you should do the same thing with PSA. Doctors should order the PSA tests in the right group of people. If the PSA is less than 1.5, no discussion is needed. Tell the man to come back in five years.

If his PSA is greater than 1.5, we need the next layer of testing and discussion. The goal right now is simple.

PSA is a frontline test to help identify people at risk for having prostate cancer. PSA doesn’t tell us what kind of risk. It doesn’t tell us if the man has low- grade or high-grade prostate cancer. That is where some of these new tests come in. PSA screening by itself, without any further testing, is gone. PSA is just the first test.

If a doctor were considering doing a biopsy and worried about prostate cancer, the next step would be genomic testing.

What sorts of genomic testing would be appropriate in this setting?

Dr. Crawford: The tests fall into three buckets: blood-based, urine-based, and tissue-based.

The ones I’m working on now are either blood- or urine-based tests. The prostate health index (PHI) is a formula that looks at several forms of PSA to come up with the relative risk of having prostate cancer. Phi is FDA-approved in the US for use in men with a PSA above 4: it gives their relative risk of having prostate cancer.

There are two issues with PHI. First, in Europe, the PSA cutoff is 2. In the United States, the PSA cutoff is 4. But we still have a lot of prostate cancer in men with a PSA between 1.5 and 4. We published a paper that showed a 10-13% higher risk in men with a PSA between 1.5 and 4.

Second, we need more data on PHI levels and high-grade cancers. We’ve done some studies that show that there seems to be a good correlation between high PHI levels and high-grade cancers.

The other test is 4Kscore, which looks at the four prostate-specific kallikreins in the blood: Total PSA, Free PSA, Intact PSA, and Human Kallikrein 2 (hK2). The company adds their secret sauce and gives your relative risk of having high-grade prostate cancer.

If your 4Kscore is less than 7%, you don’t worry. Above 7%, you do. Still, some people have high-grade cancer when their 4Kscore is below that—you have to account for other risk factors—but it’s another good blood test. It’s easy to do. The cost is down to less than $700 now. They’re trying to get Medicare coverage.

Another test is the urine-based test SelectMDx. This test is done after a digital rectal exam. It is based on two genes that are overexpressed in high-grade prostate cancer. You measure the messenger RNA in urine.

What I like about SelectMDx is that if the test comes back negative, it has a 99% negative predictive value that you don’t have a high-grade cancer like a Gleason grade 8, 9, or 10 and a 98% chance you don’t have a Gleason 7 or above cancer.

If the SelectMDx comes back negative, it makes you feel really good. If it comes back positive, it gives you a relative risk of low-grade and high-grade cancers. The aim is to find the higher- grade cancers.

Right now, I think one of the more promising genomic tests is the SelectMDx.

Why so much of a push to develop these molecular markers?

Dr. Crawford: It’s time. This is the era of personalized medicine. This is a way of addressing the issue of overdiagnosis and overtreatment.

There are approximately 1.4 million prostate biopsies done in the United States every year, but we only diagnose a couple hundred thousand people with prostate cancer. Many get rebiopsied and rebiopsied and rebiopsied.

If your biopsy is positive and you’ve picked up a low-grade cancer, you might then choose a molecular marker to determine your cancer’s aggressiveness. These are the tissue-based genomic tests, such as Oncotype DX, Prolaris, and Decipher.

Another is called ConfirmMDx. This is a tissue-based test that looks for genetic changes called methylation genes around the cancer. (These are areas of cancerization.)

If the biopsy is negative and we order ConfirmMDx on the tissue and that test comes back as positive, it means we’ve widened the target area: we may have missed something and need to go back and look again with another biopsy.

Are prostate cancer markers covered by insurance?

Dr. Crawford: Only PHI and PCA3 have been approved. (PCA3 has pretty much gone by the wayside, though, after the introduction of SelectMDx.)

It happens this way: the company does some clinical trials, they bill insurance, and then they submit to Medicare. They get local coverage determination in which the test will be covered for a period of time while they continue to investigate.

The companies who make these markers are not big companies with deep pockets. They have a limited budget.

If we wait for an endpoint of death on some of these studies, none of us will be around to see the results. We need to think about other endpoints. We are looking at these other endpoints.

I’m excited about all this. I think we’ve got a way forward now. Most family practitioners believe that screening does do some good, but they know that it also does some harm. Now that we’ve got the tools to deal with screening, let’s deal with it. Patients believe in screening. We don’t want to go back to where we were with metastatic disease being the norm.

Do you think the former recommendation against screening ended up having a positive impact? That it forced the prostate cancer community to reevaluate the issue of overtreatment?

Dr. Crawford: A lot of people don’t think that, but I do. There was a lot of overdiagnosis and overtreatment.

Sometimes when you tell a man he has cancer, he wants it taken care of yesterday. Many don’t understand that some prostate cancers are like skin cancers. You don’t cut off your arm because you have a small basal cell cancer on your wrist. It’s the same way with prostate cancer. There are low-grade, nonthreatening Gleason 6 cancers.

Are these prostate cancer markers now widely accepted among family practitioners?

Dr. Crawford: No. Family practice doctors don’t know much about these markers at all. Urologists don’t either. This is the beginning of a long educational process. It’ll take patients asking about the tests. Often, patients drive change: that’s just the way things happen.

Many of our readers are influential in their communities. What would you say to those men about getting the word out about prostate cancer markers?

Dr. Crawford: There are a lot of hereditary and germline mutations being put forth in prostate cancer: as many as 5% up to 20% of prostate cancer patients will have some of these mutations.

One of my recommendations is that if you have germline mutations of prostate cancer like BRCA2 (and others) your family members should get tested.

The PSA cutoff of 1.5 falls in very nicely with this. If your PSA is 1.5 or above, get the tests we discussed— like the SelectMDx or the 4K.

What about repeating these tests? If a man consistently has a high PSA, would it make sense to keep repeating these tests?

Dr. Crawford: He should be referred to a urologist.

Are these tests at all useful in men on active surveillance or with low-grade cancers?

Dr. Crawford: Thirty percent of patients fail active surveillance. When these men eventually have surgery, sometimes they have adverse pathology. Why did that happen? It happened because when we did the biopsy, we missed the bad cancer—the Gleason 7s, 8s, 9s, and 10s. Some of these tissue markers, like Prolaris and Oncotype DX, can help in that scenario.

Part of the follow-up for men on active surveillance is a repeat biopsy. I haven’t met a lot of men who like to have biopsies every year, but they do it.

After a while, doing repeat biopsies and monitoring gets to be more expensive than treatment. A urine test like SelectMDx or 4K can help you determine who needs to be rebiopsied.

What I’m looking at now is whether or not doing the SelectMDx every other year can eliminate the need for biopsies. And I’m finding the answer is yes.